Taxol (1) is a natural product isolated from the Pacific yew tree (Taxus brevifolia). It was first isolated in 1971 from the western yew, Taxus brevifolia by Wani et al. (J. Am. Chem. Soc., 1971, 93, 2325), who characterized its structure by chemical and X-ray crystallographic methods.
Taxol was recently approved for treatment of ovarian cancer patients. Insolubility problems with this drug, however, have prompted attempts to improve its pharmacological profile.
Taxol and various taxane derivatives (collectively herein referred to as "taxols") are highly cytotoxic and possess strong in vivo activities in a number of leukemic and tumor systems. Especially, taxol (1) is considered an exceptionally promising cancer chemotherapeutic agent, and is currently in phase II clinical trials in the United States. Equally important is taxotere (2) (L. Mangatal et al., Tetrahedron, 1989, 45, 4177), a semisynthetic analog of taxol which is also undergoing clinical trails with impressive results. Clinical results have demonstrated high efficacy of taxols against such cancer types as ovarian, lung, gastric, breast, colon and cervical carcinomas.
Taxol is a member of the taxane family of diterpenes having the following structure: ##STR2##
A synthetic analog of taxol has the following structure: ##STR3##
Taxol is only slightly soluble in water and this has created significant problems in developing suitable pharmaceutical formulations useful for chemotherapy. Some formulations of taxol for injection or I.V. infusion have been developed utilizing CREMOPHOR EL.RTM. (polyoxyethylated castor oil) as the drug carrier because of taxol's aqueous insolubility. For example, taxol supplied by the NCI has been formulated in 50% CREMOPHOR EL.RTM. and 50% dehydrated alcohol. CREMOPHOR EL.RTM., however, is itself toxic and produces, when given in a large volume single dose without taxol, vasodilation, labored breathing, lethargy, hypotension and death in dogs. Therefore, the use of this carrier would not be recommended.
In an attempt to increase taxol's solubility and to develop more safe clinical formulations, studies have been directed to synthesizing taxol analogs where 2'- and/or 7-position is derivatized with groups that would enhance water solubility. These efforts yielded protaxol compounds that are more water soluble than the parent compound and that deplay the cytotoxic properties upon activation.
U.S. Pat. No. 4.942.184 to R. D. Haugwitz, et al. discloses water soluble taxols having variously substituted acyl groups at 2'-O-position.
U.S. Pat. No. 4.960.790 to V. J. Stella, et al. discloses water soluble taxols the 2'- and/or 7-hydroxyl of which is derivatized with a selected amino acid or an amino acid mimetic compound.
Structure-activity relationships and solubility improvements of taxol have been probed through substitution at the C-2' hydroxyl group. For example, H. M. Deutsch et al. disclosed the synthesis of water-soluble prodrugs of Taxol with potent antitumor activity, Journal of Medical Chemistry (1989) 32, 788-792. More recent efforts to this end were also disclosed by Charles Swindell et al. (Journal of Medical Chemistry (1991) 34, 1176-1184), by Zhiyang Zhao et al. (Journal of Natural Products (1991) 54, 1607-1611) and by Abraham E. Mathew et al. (Journal of Medical Chemistry (1992) 35, 145-151). However, none of the prodrugs disclosed in the prior art exhibited sensitivity to alkaline hydrolysis under physiological conditions. This absence of sensitivity compromises their utility as pharmacological agents.
Accordingly, it is apparent that it would have been desirable to develop protaxol derivatives which would be more water soluble than taxol, but which, upon hydrolysis under physiological (alkaline) conditions, would exhibit the same or similar level of antitumor activity as unmodified taxol. Furthermore, the rate of hydrolysis should facilitate the pharmacokinetics of the drug so as to enhance its delivery. The present invention achieves this goal by providing protaxol derivatives that are water soluble and that are susceptible, under physiological conditions, to a novel mechanism of controlled hydrolysis for providing the bioactive form of taxol at a pharmacokinetically favorable rate.